Interleukin-1 increases protein kinase A activity by a cAMP-independent mechanism in AtT-20 cells

1994 ◽  
Vol 266 (1) ◽  
pp. E79-E84 ◽  
Author(s):  
A. R. Gwosdow ◽  
N. A. O'Connell ◽  
A. B. Abou-Samra
Keyword(s):  
Protein Kinase ◽  
Adenylate Cyclase ◽  
Protein Kinase A ◽  
Interleukin 1 ◽  
Phosphodiesterase Inhibitor ◽  
Intracellular Camp ◽  
Camp Accumulation ◽  
Acth Secretion ◽  
Intracellular Camp Accumulation ◽  
Kinase A

A recent study from this laboratory has shown that the inflammatory mediator, interleukin-1 alpha (IL-1 alpha), stimulates protein kinase A (PKA) activity and adrenocorticotropic hormone (ACTH) secretion from AtT-20 cells without any detectable increase in intracellular cAMP accumulation. The present studies were conducted to determine if cAMP is involved in IL-1 alpha activation of PKA and if PKA is responsible for IL-1 alpha-induced ACTH release from AtT-20 cells. The data are consistent with a novel mechanism of PKA activation that does not involve cAMP. Inhibition of adenylate cyclase with 2'5'-dideoxyadenosine (2'5'-DDA) did not affect IL-1 alpha-induced increases in PKA activity and ACTH secretion. In contrast, CRF-stimulated PKA activity and ACTH secretion were inhibited by 2'5'-DDA. Additional evidence was obtained using the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). IBMX did not alter IL-1 alpha-induced PKA activity or ACTH secretion, yet IBMX potentiated CRF-induced cAMP accumulation. Inhibition of PKA with the PKA inhibitor, H-8, blocked activation of PKA and ACTH secretion by both IL-1 alpha and CRF in AtT-20 cells. These observations demonstrate that 1) the mechanism of IL-1 alpha activation of PKA is independent of adenylate cyclase or cAMP and 2) PKA is used by IL-1 alpha to induce ACTH secretion from AtT-20 cells.

Interleukin-1 alpha stimulates dopamine release by activating type II protein kinase A in PC-12 cells

1995 ◽  
Vol 269 (6) ◽  
pp. E1083-E1088
Author(s):  
A. Joseph ◽  
A. Kumar ◽  
N. A. O'Connell ◽  
R. K. Agarwal ◽  
A. R. Gwosdow
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Dopamine Release ◽  
Interleukin 1 ◽  
Intracellular Camp ◽  
Type I ◽  
Camp Accumulation ◽  
Type Ii ◽  
Pc 12 Cells ◽  
Kinase A

A recent study from this laboratory [A. R. Gwosdow, N. A. O'Connell, and A. B. Abou-Samra. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E461-E466, 1992] showed that the inflammatory mediator interleukin-1 alpha (IL-1 alpha) stimulates catecholamine release from primary cultures of rat adrenal cells. The present studies were conducted to determine whether 1) IL-1 alpha stimulates catecholamine/dopamine release from the adrenal medullary cell line PC-12 and 2) the adenosine 3',5'-cyclic monophosphate (cAMP)-protein kinase A (PKA) pathway is involved in IL-1 alpha-induced dopamine release from PC-12 cells. The results indicate that IL-1 alpha significantly (P < 0.05) elevated dopamine release after a 24-h incubation period. IL-1 alpha did not stimulate cAMP accumulation at any time period between 5 min and 2 h. In contrast, forskolin-treated cells elevated (P < 0.05) intracellular cAMP levels and increased dopamine release. Because IL-1 alpha did not affect cAMP accumulation, the effect of IL-1 alpha on PKA activity was investigated. IL-1 alpha increased (P < 0.05) PKA activity at 15 and 30 min and returned to control levels by 1 h. Forskolin also increased (P < 0.05) PKA activity. The type of PKA activated (P < 0.05) by IL-1 alpha was type II PKA. In contrast, forskolin activated (P < 0.05) type I and type II PKA. Inhibition of PKA with the PKA inhibitor H-8 blocked PKA activity and dopamine secretion by both IL-1 alpha and forskolin in PC-12 cells. These observations demonstrate that 1) IL-1 alpha stimulated dopamine release from PC-12 cells by activating PKA, 2) the mechanism of IL-1 alpha activation of PKA does not involve detectable increases in intracellular cAMP accumulation, and 3) IL-1 alpha activates type II PKA, which is used by IL-1 alpha to stimulate dopamine secretion from PC-12 cells.

scholarly journals Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation

2011 ◽  
Vol 435 (3) ◽  
pp. 755-769 ◽  
Author(s):  
Kirsty F. MacKenzie ◽  
Derek A. Wallace ◽  
Elaine V. Hill ◽  
Diana F. Anthony ◽  
David J. P. Henderson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
P38 Mapk ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Intracellular Camp ◽  
Camp Accumulation ◽  
Kinase A

cAMP-specific PDE (phosphodiesterase) 4 isoforms underpin compartmentalized cAMP signalling in mammalian cells through targeting to specific signalling complexes. Their importance is apparent as PDE4 selective inhibitors exert profound anti-inflammatory effects and act as cognitive enhancers. The p38 MAPK (mitogen-activated protein kinase) signalling cascade is a key signal transduction pathway involved in the control of cellular immune, inflammatory and stress responses. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP. Such reprogramming of cAMP accumulation is recapitulated in wild-type primary macrophages, but not MK2/3-null macrophages. Phosphorylation by MK2 also triggers a conformational change in PDE4A5 that attenuates PDE4A5 interaction with proteins whose binding involves UCR2, such as DISC1 (disrupted in schizophrenia 1) and AIP (aryl hydrocarbon receptor-interacting protein), but not the UCR2-independent interacting scaffold protein β-arrestin. Long PDE4 isoforms thus provide a novel node for cross-talk between the cAMP and p38 MAPK signalling systems at the level of MK2.

scholarly journals Intracellular adenosine 3′,5′-phosphate formation is essential for down-regulation of surface adenosine 3′,5′-phosphate receptors in Dictyostelium

1994 ◽  
Vol 303 (2) ◽  
pp. 539-545 ◽  
Author(s):  
P J M Van Haastert
Keyword(s):  
Protein Kinase ◽  
Adenylate Cyclase ◽  
Protein Kinase A ◽  
Intracellular Camp ◽  
Down Regulation ◽  
Prolonged Incubation ◽  
Surface Receptors ◽  
Surface Receptor ◽  
Mutant Cells ◽  
Kinase A

Dictyostelium discoideum cells contain cell surface cyclic AMP (cAMP) receptors that bind cAMP as a first messenger and intracellular cAMP receptors that bind cAMP as a second messenger. Prolonged incubation of Dictyostelium cells with cAMP induces a sequential process of phosphorylation, sequestration and down-regulation of the surface receptors. The role of intracellular cAMP in down-regulation of surface receptors was investigated. Down-regulation of receptors does not occur under conditions that specifically inhibit the formation of intracellular cAMP (the drug caffeine or mutant cells lacking adenylate cyclase) or conditions that inhibit the function of intracellular cAMP (mutants lacking protein kinase A activity). Cell-permeable non-hydrolysable cAMP derivatives were used to investigate further the requirement of intracellular cAMP for down-regulation. The Sp isomer of 6-thioethylpurineriboside 3′,5′-phosphorothioate (6SEth-cPuMPS) does not bind to the surface receptor, enters the cell and has relative high affinity for protein kinase A. 6SEth-cPuMPS alone has no effect on down-regulation. However, together with an agonist of the surface receptor, the analogue induces down-regulation in caffeine-treated wild-type cells and in mutant cells lacking adenylate cyclase, but not in mutant cells lacking protein kinase A. These results indicate that intracellular cAMP formation and activation of protein kinase A are essential for down-regulation of the surface cAMP receptor.

scholarly journals Phosphodiesterase Inhibitors SuppressLactobacillus caseiCell-Wall-Induced NF-κB and MAPK Activations and Cell Proliferation through Protein Kinase A—or Exchange Protein Activated by cAMP-Dependent Signal Pathway

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Takekatsu Saito ◽  
Naotoshi Sugimoto ◽  
Kunio Ohta ◽  
Tohru Shimizu ◽  
Kaori Ohtani ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Signaling Pathways ◽  
Inflammatory Responses ◽  
Phosphodiesterase Inhibitor ◽  
Mapk Signaling ◽  
Intracellular Camp ◽  
Kinase A ◽  
Exchange Protein

Specific strains ofLactobacillushave been found to be beneficial in treating some types of diarrhea and vaginosis. However, a high mortality rate results from underlying immunosuppressive conditions in patients withLactobacillus caseibacteremia. Cyclic AMP (cAMP) is a small second messenger molecule that mediates signal transduction. The onset and progression of inflammatory responses are sensitive to changes in steady-state cAMP levels.L. caseicell wall extract (LCWE) develops arteritis in mice through Toll-like receptor-2 signaling. The purpose of this study was to investigate whether intracellular cAMP affects LCWE-induced pathological signaling. LCWE was shown to induce phosphorylation of the nuclear factorκB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways and cell proliferation in mice fibroblast cells. Theophylline and phosphodiesterase inhibitor increased intracellular cAMP and inhibited LCWE-induced cell proliferation as well as phosphorylation of NF-κB and MAPK. Protein kinase A inhibitor H89 prevented cAMP-induced MAPK inhibition, but not cAMP-induced NF-κB inhibition. An exchange protein activated by cAMP (Epac) agonist inhibited NF-κB activation but not MAPK activation. These results indicate that an increase in intracellular cAMP prevents LCWE induction of pathological signaling pathways dependent on PKA and Epac signaling.

scholarly journals Pituitary adenylate cyclase activating polypeptide as a novel hypophysiotropic factor in fish

2000 ◽  
Vol 78 (3) ◽  
pp. 329-343 ◽  
Author(s):  
Anderson OL Wong ◽  
Wen Sheng Li ◽  
Eric KY Lee ◽  
Mei Yee Leung ◽  
Lai Yin Tse ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Adenylate Cyclase ◽  
Protein Kinase A ◽  
Anterior Pituitary ◽  
Kinase C ◽  
Pituitary Adenylate Cyclase ◽  
Pacap Receptors ◽  
Kinase A

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel member of the secretin-glucagon peptide family. In mammals, this peptide has been located in a wide range of tissues and is involved in a variety of biological functions. In lower vertebrates, especially fish, increasing evidence suggests that PACAP may function as a hypophysiotropic factor regulating pituitary hormone secretion. PACAP has been identified in the brain-pituitary axis of representative fish species. The molecular structure of fish PACAP is highly homologous to mammalian PACAP. The prepro-PACAP in fish, however, is distinct from that of mammals as it also contains the sequence of fish GHRH. In teleosts, the anterior pituitary is under direct innervation of the hypothalamus and PACAP nerve fibers have been identified in the pars distalis. Using the goldfish as a fish model, mRNA transcripts of PACAP receptors, namely the PAC1 and VPAC1 receptors, have been identified in the pituitary as well as in various brain areas. Consistent with the pituitary expression of PACAP receptors, PACAP analogs are effective in stimulating growth hormone (GH) and gonadotropin (GTH)-II secretion in the goldfish both in vivo and in vitro. The GH-releasing action of PACAP is mediated via pituitary PAC1 receptors coupled to the adenylate cyclase-cAMP-protein kinase A and phospholipase C-IP3-protein kinase C pathways. Subsequent stimulation of Ca2+ entry through voltage-sensitive Ca2+ channels followed by activation of Ca2+-calmodulin protein kinase II is likely the downstream mechanism mediating PACAP-stimulated GH release in goldfish. Although the PACAP receptor subtype(s) and the associated post-receptor signaling events responsible for PACAP-stimulated GTH-II release have not been characterized in goldfish, these findings support the hypothesis that PACAP is produced in the hypothalamus and delivered to the anterior pituitary to regulate GH and GTH-II release in fish.Key words: PACAP, VIP, PAC1 receptor, VPAC1 receptor, VPAC2 receptor, growth hormone, gonadotropin-II, cAMP, protein kinase A, protein kinase C, calcium, pituitary cells, goldfish, and teleost.

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